The role of Peripheral CGRP in a preclinical mouse model of migraine

外周 CGRP 在偏头痛临床前小鼠模型中的作用

• 批准号: 9332208
• 负责人: Bianca N Mason
• 金额: $ 2.38万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2017-12-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9332208
• 关键词: Affect; American; Behavior; Behavioral; Blood Pressure; Blood Vessels; Brain region; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Cells; Closure by clamp; Complex; Data; Development; Diagnostic; Disease; Face; Future; Genetic; Injectable; Injection of therapeutic agent; Laboratories; Light; Measures; Meninges; Migraine; Monoclonal Antibodies; Mus; Nerve Tissue; Nervous system structure; Neural Pathways; Neuraxis; Neurons; Neuropeptides; Outcome; Pain; Pathogenesis; Patients; Pattern; Perception; Peripheral; Pharmacologic Substance; Pharmacology; Phenotype; Photophobia; Pre-Clinical Model; Quality of life; Research; Role; Sensory; Signal Transduction; Site; Smooth Muscle Myocytes; Structure; Symptoms; Synaptic Transmission; System; Testing; Thalamic structure; Tissues; Transgenes; Transgenic Mice; Trigeminal Nuclei; Trigeminal System; Trigeminal nerve structure; Vascular Endothelial Cell; Vascular Smooth Muscle; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Wild Type Mouse; base; design; experience; genetic approach; human subject; immunoreactivity; individualized medicine; insight; interest; intraperitoneal; intravenous administration; mast cell; mouse model; nervous system disorder; nestin protein; overexpression; pre-clinical; prevent; receptor expression; response; somatosensory

Project Summary/Abstract Migraine is a complex and debilitating neurological disorder involving the neuropeptide calcitonin gene- related peptide (CGRP). The overall objective of this project is to identify mechanisms by which peripheral CGRP causes photophobia, a painful response to non-noxious levels of light experienced by ~90% of migraine patients. Peripheral injection of CGRP causes light aversion, a response analogous to photophobia. This response in wild-type requires bright light, while in transgenic mice with globally increased CGRP receptors there is an enhanced response seen even in dim light. Interestingly, this enhanced light aversive phenotype is not seen in transgenic mice that have elevated nervous system expression of the receptor. This evidence suggests that peripheral CGRP administration may cause light aversion and activate neural pathways in an indirect mechanism. Since CGRP is one of the most potent vasodilators in the body, we hypothesize that CGRP can cause light aversion by a vascular mechanism. This hypothesis is based on findings that 1) intravenous administration of CGRP in human subjects can cause migraine pain, and 2) perivascular CGRP can sensitize the trigeminal nerve, which could alter synaptic transmission to the central nervous system. Thus, there is a mechanism by which CGRP in the periphery can sensitize the trigeminal nerve and alter sensory perception, leading to photophobia. A single aim is proposed that will establish the contribution of the vasculature in light aversive behavior. Complementary pharmacological and genetic strategies will be used. The pharmacological approach will be to co-administer a vasoconstrictor to minimize CGRP-induced vasodilation. The genetic approach will be to generate transgenic mice with conditional overexpression of CGRP receptors on endothelial and smooth muscle cells of the vasculature. This aim will provide insight into the mechanisms by which peripheral CGRP can trigger a migraine-like symptom in a preclinical mouse model of migraine.

项目总结/文摘